Tang Yiting, Zhang Fangfang, Huang Ling, Yuan Qiongjing, Qin Jiao, Li Bingxin, Wang Nasui, Xie Yanyun, Wang Linghao, Wang Wei, Kwan Kevin, Peng Zhangzhe, Hu Gaoyun, Li Jing, Tao Lijian
Division of Nephrology (YT, FZ, LH, QY, JQ, BL, NW, YX, LW, WW, ZP, LT), Xiangya Hospital, Central South University, Changsha, Hunan, China; School of Pharmaceutical Sciences (GH), Central South University, Changsha, Hunan, China; State Key Laboratory of Medical Genetics of China (LT), Changsha, Hunan, China; Sunshine Lake Pharma Co, Ltd (JL), Guangdong, China; Surgical Department, North Shore University Hospital (KK), Manhasset, New York; and Central South University, Changsha, China.
Am J Med Sci. 2015 Sep;350(3):195-203. doi: 10.1097/MAJ.0000000000000501.
Deregulated inflammation has been implicated in the development of renal interstitial fibrosis and progressive renal failure. Previous work has established that fluorofenidone, a pyridone agent, attenuates renal fibrosis. However, the mechanism by which fluorofenidone prevents renal fibrosis remains unclear. The aim of this study was to investigate the in vivo effects of fluorofenidone on unilateral ureteral obstruction-induced fibrosis and the involved molecular mechanism in mouse peritoneal macrophages.
Renal fibrosis was induced in rat by unilateral ureteral obstruction for 3, 7 or 14 days. Ipsilateral kidneys were harvested for morphologic analysis. Leukocyte infiltration was assessed by immunohistochemistry staining. The expression of chemokines (MCP-1, RANTAS, IP-10, MIP-1α and MIP-1β) and pro-inflammatory cytokines (TNF-α and IL-1β) was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mouse peritoneal macrophages and HK-2 cells were incubated with necrotic MES-13 cells or TNF-α in the presence or absence of fluorofenidone. The production of MCP-1 was measured by enzyme-linked immunosorbent assay, and phosphorylation of ERK1/2, p38 and JNK was quantified by Western blot.
Fluorofenidone treatment hampered renal pathologic change and interstitial collagen deposition. Leukocyte infiltration and the expression of chemokines (MCP-1, RANTES, IP-10, MIP-1α and MIP-1β) and pro-inflammatory cytokines (IL-1α) in kidney were significantly reduced by fluorofenidone treatment. Mechanistically, fluorofenidone significantly inhibited TNF-α or necrotic cell-induced activation of MAP kinase pathways in vitro.
Fluorofenidone serves as a novel anti-inflammatory agent that attenuates ureteral obstruction-induced renal interstitial inflammation and fibrosis, possibly through the inhibition of the microtubule-associated protein kinase pathways.
炎症失调与肾间质纤维化和进行性肾衰竭的发展有关。先前的研究已经证实，吡啶酮类药物氟非尼酮可减轻肾纤维化。然而，氟非尼酮预防肾纤维化的机制仍不清楚。本研究旨在探讨氟非尼酮对单侧输尿管梗阻诱导的纤维化的体内作用以及在小鼠腹腔巨噬细胞中涉及的分子机制。
通过单侧输尿管梗阻3、7或14天在大鼠中诱导肾纤维化。收集同侧肾脏进行形态学分析。通过免疫组织化学染色评估白细胞浸润。通过酶联免疫吸附测定和实时聚合酶链反应测量趋化因子（MCP-1、RANTAS、IP-10、MIP-1α和MIP-1β）和促炎细胞因子（TNF-α和IL-1β）的表达。在存在或不存在氟非尼酮的情况下，将小鼠腹腔巨噬细胞和HK-2细胞与坏死的MES-13细胞或TNF-α一起孵育。通过酶联免疫吸附测定测量MCP-1的产生，并通过蛋白质印迹法定量ERK1/2、p38和JNK的磷酸化。
氟非尼酮治疗可阻碍肾脏病理变化和间质胶原沉积。氟非尼酮治疗可显著减少肾脏中的白细胞浸润以及趋化因子（MCP-1、RANTES、IP-10、MIP-1α和MIP-1β）和促炎细胞因子（IL-1α）的表达。从机制上讲，氟非尼酮在体外可显著抑制TNF-α或坏死细胞诱导的丝裂原活化蛋白激酶途径的激活。
氟非尼酮作为一种新型抗炎药，可能通过抑制微管相关蛋白激酶途径减轻输尿管梗阻诱导的肾间质炎症和纤维化。
